Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin, People's Republic of China.
The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, People's Republic of China.
Blood Adv. 2022 Aug 9;6(15):4617-4633. doi: 10.1182/bloodadvances.2022006980.
Early hemorrhagic death is still the main obstacle for the successful treatment of acute promyelocytic leukemia (APL). However, the mechanisms underlying hemostatic perturbations in APL have not been fully elucidated. Here, we report that CD44 on the membrane of APL blasts and NB4 cells ligated bound fibrinogen, resulting in in situ deposition of fibrin and abnormal fibrin distribution. Clots formed by leukemic cells in response to CD44 and fibrinogen interaction exhibited low permeability and resistance to fibrinolysis. Using flow cytometry and confocal microscopy, we found that CD44 was also involved in platelet and leukemic cell adhesion. CD44 bound activated platelets but not resting platelets through interaction with P-selectin. APL cell-coated fibrinogen-activated platelets directly induce enhanced procoagulant activity of platelets. In vivo studies revealed that CD44 knockdown shortened bleeding time, increased the level of fibrinogen, and elevated the number of platelets by approximately twofold in an APL mouse model. Moreover, CD44 expression on leukemic cells in an APL mouse model was not only associated with bleeding complications but was also related to the wound-healing process and the survival time of APL mice. Collectively, our results suggest that CD44 may be a potential intervention target for preventing bleeding complications in APL.
早期出血性死亡仍然是急性早幼粒细胞白血病 (APL) 成功治疗的主要障碍。然而，APL 中止血紊乱的机制尚未完全阐明。在这里，我们报告 APL 原始细胞和 NB4 细胞上的膜结合纤维蛋白原的 CD44 结合，导致纤维蛋白原位沉积和异常纤维蛋白分布。对 CD44 和纤维蛋白原相互作用的白血病细胞形成的血栓表现出低通透性和抗纤维蛋白溶解的能力。通过流式细胞术和共聚焦显微镜，我们发现 CD44 还参与血小板和白血病细胞的黏附。CD44 通过与 P-选择素相互作用结合激活的血小板，但不结合静止的血小板。APL 细胞包被的纤维蛋白原激活的血小板直接诱导血小板增强的促凝活性。体内研究表明，在 APL 小鼠模型中，CD44 敲低缩短了出血时间，增加了纤维蛋白原水平，并将血小板数量增加了大约两倍。此外，APL 小鼠模型中白血病细胞上的 CD44 表达不仅与出血并发症有关，还与伤口愈合过程和 APL 小鼠的生存时间有关。总之，我们的结果表明 CD44 可能是预防 APL 出血并发症的潜在干预靶点。
